Many commercially valuable compounds are isolated as their acid addition salts; for instance their hydrochloride, hydrobromide or acetate salts. This is especially true in the pharmaceutical industry where many pharmaceuticals are marketed in their salt forms. Examples include terazosin hydrochloride (2-[(4-tetrahydro-2-furoyl)-1-piperazinyl]-4-amino-6,7-di-methoxyquinazoline hydrochloride, 1), flecainide acetate (N-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxybenzamide acetate 2) and ranitidine hydrochloride (N-[2-[[[-5-[(dimethylamino)methyl]-2-furanyl]-methyl]thio]ethyl]-N′-methyl-2-nitro-1,1-ethenediamine hydrochloride, 3). Also, other compounds such as domperidone (5-chloro-1-[1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-yl)-propyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 4) are marketed as their free base.

Typically in the prior art, the method of salt formation involved dissolution of the basic compound in a solvent followed by addition of the acid component. However, this would often lead to incorporation of the solvent of dissolution in the acid addition salt upon crystallization or precipitation. Noteworthy is that the preparation of active pharmaceutical ingredients (API's) must meet high purity specifications, for instance in terms of residual solvent content and to this end, regulatory authorities have set out quality guidelines regarding the permissible amounts of residual solvent in active pharmaceutical ingredients (for example, International Conference on Harmonisation, guideline Q3C). In this respect, a dry process (i.e. one which does not employ solvent) for the formation of a hydrochloride, hydrobromide or acetate salt for instance, which would minimize the possibility of residual solvent contamination, would be highly advantageous. The avoidance of solvent also offers an advantage in terms of reduced cost to prepare the product, better reactor throughput due to reduced volumes, and improved safety since many solvents have known toxicities and are flammable. It also represents a more environmentally friendly, or ‘green’ process.
Kaupp, G., Schmeyers, J. and Boy, J. have reported various types of reactions using gas/solid reactions including the addition of hydrogen halides. This work is reviewed in “Waste-free solid-state syntheses with quantitative yield”, Chemosphere, Vol. 43 (2001), pp. 55-61. Specifically, Table 1 on page 56 summarizes the types of solid-state reactions examined by Kaupp. A specific example of salt formation on an amino-substrate is found in an earlier publication by Kaupp, G., Pogodda, U. and Schmeyers. J.; namely “Gas/solid Reactions with Acetone”, Chem. Ber., (1994), Vol. 127, pp. 2249-2261 where bis-hydrohalide salts of ortho-phenylenediamine substrates were prepared. The highly reactive microcrystalline compounds formed were further reacted with acetone in the gaseous state to form dihydrohalides of their respective 1,5-benzodiazepines by reaction with acetone followed by cyclization and loss of water. Also, an example of hydrohalide salt formation on benzothiazole-substrates is given in Kaupp. G., Lübben, D. and Sauerland, O., “Gas/Solid-Reactions with Sulfur Compounds”, Phosphorus, Sulfur, and Silicon, (1990), Vol. 53. pp. 109-120).
Thus, the establishment of a novel methods for acid addition salt preparation of commercially important materials such as active pharmaceutical ingredients is desirable.